The present invention relates to 1-N-phenylamino-1H-imidazole derivatives and to pharmaceutical compositions containing them.
The invention generally relates to the field of hormone- and non hormone-dependent cancer and endocrine disorders.
Aromatase is the physiological enzyme responsible for the specific conversion of androgens such as androstenedione or testosterone, into estrogens such as estrone and estradiol, respectively (Simpson E R et al., Endocrine Reviews, 1994, 15: 342-355). Inhibition of aromatase is, therefore, a strategy of choice to interfere with normal or pathological estrogen-induced or estrogen-dependent biological processes such as female sexual differentiation, ovulation, implantation, pregnancy, breast and endometrial cell proliferation as well as regulations of spermatogenesis or prostate cell proliferation in male or of non-reproductive functions such as bone formation or immune T cell and cytokine balance (see Simpson E R et al., Recent Progress in Hormone Research, 1997, 52: 185-213 and the whole issues of Endocrine Related Cancer (1999, volume 6, no 2) and Breast Cancer Research Treatment (1998, volume 49, supplement no 1)).
The enzyme steroid sulfatase (E.C. 3.1.6.2, STS) catalyses the hydrolysis of estrone sulfate to estrone and the DHEA sulfate to DHEA (Dibbelt L, Biol. Chem, Hoppe-Seyler, 1991, 372, 173-185 and Stein C, J. Biol. Chem., 1989, 264, 13865-13872).
The steroid sulfatase pathway has been the focus of recent interest in the context of breast cancer, with regard to the local intra-tissue formation of estrogens from the abundant circulating pool of estrone sulfate (E1S) (Pasqualini J R, J. Steroid Biochem. Mol. Biol., 1999, 69, 287-292 and Purohit A, Mol. Cell. Endocrinol., 2001, 171, 129-135).
Inhibition of this enzyme would prevent EIS from yielding free estrone (E1), which can be transformed into estradiol (E2) by enzymatic reduction. In addition to the estrone sulfatase pathway, it is now believed that another potent estrogen, androstenediol (adiol) obtained from DHEA after hydrolysis of DHEA-S, could be another important contributor, in the support of growth and development of hormone-dependent breast tumors.
The formation of estrogens in women is schematically represented in FIG. 1.
In patients with hormone-dependent cancers, aromatase inhibitors are currently used to prevent estrogen synthesis. However, clinical trials showed a relative lack of efficacy for patients with estrogen receptor-positive tumors (Castiglione-Gertsch M, Eur. 3. Cancer, 1996, 32A, 393-395 and Jonat W, Eur. J. Cancer, 1996, 32A, 404-412). As an explanation, steroid sulfatase pathway could be another important route for estrogen formation in breast tumors.
EMATE (Ahmed S, Curr. Med. Chem., 2002, 9, 2, 263-273), estrone-3-sulfamate, is the historical standard steroidal sulfatase inhibitor but has the major drawback of being estrogenic because of its mechanism of inhibition: the sulfamate moiety is cleaved during the process of enzyme inactivation, which releases E1, not from EIS but from EMATE itself (Ahmed S, J. Steroid Biochem. Mol. Biol., 2002, 80, 429-440).

Other non-steroid sulfamate compounds which release derivatives without estrogenic properties have been presented as acceptable drug candidates such as 6,6,7-COUMATE, a standard non-estrogenic sulfatase inhibitor from the literature (Purohit A, Cancer Res, 2000, 60, 3394-3396).

Human carbonic anhydrases catalyse the conversion between carbon dioxide (CO2) and the bicarbonate ion (HCO3−), and are involved in physiological and pathological processes. They include hormone-dependent and non-hormone-dependent cancerogenesis, metastasis invasive process and hypoxic tumors that express these enzymes which are less responsive to classical chemo/radio-therapy inhibitors. In particular, EMATE was found to have a human carbonic anhydrase inhibitory potency similar to that of acetazolamide, a well-known sulfonamide human carbonic anhydrase inhibitor (Winum 3 and al., J. Med. Chem. 2003, 46, 2197-2204).
It is therefore of particular interest to have compounds with at least one, preferably at least two of the following activities: aromatase inhibition, steroid sulfatase inhibition and carbonic anhydrase inhibition.
Recently, B. Potter et al. (J. Med. Chem., 46, 2003, 3193-3196) reported that sulfamoylated-derivatives of the aromatase inhibitor YM 511 inhibited sulfatase and aromatase activity in JEG-3 cells.

Compounds presented as useful for the treatment of estrogen-dependent diseases, are described in U.S. 2003/0008862A. Imidazole derivatives with anti-aromatase properties are described in WO 2004/054983.